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International Journal of Biochemistry and Biomolecule Research Original Research Open Access

In-Silico Docking of Rubia cordifolia Phytocompounds as Potential MMP-2 Inhibitors for Varicose Vein Management

  1. K. Anusree Department of Chemistry and Biochemistry, School of Sciences, Jain (Deemed-to-be) University, Bangalore

Abstract

Varicose veins are one of the most common disorders, affecting the vein structure and function of lower limbs, yet there has been no absolute cure found yet. One of the underlying causes for worsening of the condition is the proteolytic activity of MMPs which are a group of enzymes that affect the extracellular matrix (ECM) surrounding the affected veins. Phytocompounds of Rubia cordifolia (Manjishta) were docked against the MMP-2 protein to check presence of protein-ligand interaction that can predict the possibility of using the best suited ligand as an inhibitor against MMP-2 protein. Out of a total of 37 phytochemicals 17 were found to have the most drug-like properties. The ligands were retrieved after in-silico pharmacology studies and docked against the MMP-2 protein. 6 P-L were found to have lowest BI (less than or equal to -0.9) and RMSD value of 0, which corresponds to highly stable bonding between the molecules. This study gives a possibility of using the screened ligands, Munjistine, Rubiadin, 1,5-Dihydroxy-2-Methylanthraquinone, Purpuroxanthins, Alizarin and 1-Hydroxy-2-Methoxy Anthraquinone, to study their effects on reducing the activity of MMP-2, which can reduce the progression of varicose veins into chronic venous disease.

Keywords

References (39)

  1. Nicolaides AN. The Most Severe Stage of Chronic Venous Disease: An Update on the Management of Patients with Venous Leg Ulcers. Advances in Therapy. 2020;37(S1):19-24. doi:10.1007/s12325-020-01219-y
  2. Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The Epidemiology of Chronic Venous Insufficiency and Varicose Veins. Annals of Epidemiology. 2005;15(3):175-184. doi:10.1016/j.annepidem.2004.05.015
  3. Fayyaz F, Vaghani V, Ekhator C, Abdullah M, Alsubari RA, Daher OA, et al. Advancements in Varicose Vein Treatment: Anatomy, Pathophysiology, Minimally Invasive Techniques, Sclerotherapy, Patient Satisfaction, and Future Directions. Cureus. 2024. doi:10.7759/cureus.51990
  4. Raffetto JD, Khalil RA. Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins. Vessel Plus. 2021. doi:10.20517/2574-1209.2021.16
  5. Kowalewski R, Sobolewski K, Wolanska M, Gacko M. Matrix metalloproteinases in the vein wall. Int Angiol. 2004;23(2):164–9.
  6. Johansson N, Ahonen M, Kähäri VM. Matrix metalloproteinases in tumor invasion. Cell Mol Life Sci. 2000;57(1):5–15. doi:10.1007/s000180050008
  7. W�gs�ter D. MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the Ldlr-/-Apob100/100 mouse. International Journal of Molecular Medicine. 2011. doi:10.3892/ijmm.2011.693
  8. Soini Y, Satta J, M��tt� M, Autio-Harmainen H. Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart. The Journal of Pathology. 2001;194(2):225-231. doi:10.1002/path.850
  9. Wen CC, Chen HM, Yang NS. Developing Phytocompounds from Medicinal Plants as Immunomodulators. Advances in Botanical Research. 2012:197-272. doi:10.1016/b978-0-12-394591-4.00004-0
  10. Festa J, Hussain A, Al-Hareth Z, Singh H, Da Boit M. Anthocyanins and vascular health: A matter of metabolites. Foods. 2023;12(1):47. doi:10.3390/foods12010047
  11. Kamble SC, Humbare RB, Sarkar J, Kulkarni AA. Assessment of Phytochemicals and Antioxidant Properties of Root Extracts of Rubia cordifolia L. in Different Solvent Systems. The 1st International Electronic Conference on Plant Science. 2020:100. doi:10.3390/iecps2020-08625
  12. Ali A, Aslam M, Chaudhary SS. A Review A Review on Pharmacognostic and Therapeutic Uses of Rubia cordifolia. Journal of Drug Delivery and Therapeutics. 2020;10(6):195-202. doi:10.22270/jddt.v10i6.4514
  13. Ahmad R, Fatima Z, Ali S, Dhaneshwar S, Ahmad S. HPTLC Method Development and Validation for Simultaneous Quantification of Purpurin and Alizarin in Rubia cordifolia L. Roots and their Marketed Preparations. Pharmacognosy Research. 2024;16(3):652-661. doi:10.5530/pres.16.3.76
  14. Pinzi L, Rastelli G. Molecular Docking: Shifting Paradigms in Drug Discovery. International Journal of Molecular Sciences. 2019;20(18):4331. doi:10.3390/ijms20184331
  15. RCSB Protein Data Bank. Crystal structure of human MMP-2 catalytic domain in complex with inhibitor. Available from: https://www.rcsb.org/structure/7XJO
  16. Kucukguven A, A. Khalil R. Matrix Metalloproteinases as Potential Targets in the Venous Dilation Associated with Varicose Veins. Current Drug Targets. 2013;14(3):287-324. doi:10.2174/138945013804998972
  17. Dr. Duke’s Phytochemical and Ethnobotanical Databases. Rubia cordifolia (Rubiaceae). Available from: https://phytochem.nal.usda.gov/plant-rubia-cordifolia
  18. SwissADME. Available from: http://www.swissadme.ch/
  19. Dassault Systèmes BIOVIA. Molecular modeling simulation: Discovery Studio visualization. Available from: https://www.3ds.com/products-services/biovia/products/molecular-modeling-simulation/biovia-discovery-studio/visualization
  20. Wlodawer A. Stereochemistry and Validation of Macromolecular Structures. Methods in Molecular Biology. 2017:595-610. doi:10.1007/978-1-4939-7000-1_24
  21. Ramakrishnan C, Ramachandran GN. Stereochemical Criteria for Polypeptide and Protein Chain Conformations. Biophysical Journal. 1965;5(6):909-933. doi:10.1016/s0006-3495(65)86759-5
  22. EMBL‑EBI PDBsum Procheck. Available from: https://www.ebi.ac.uk/thornton-srv/databases/pdbsum/
  23. Dallakyan S, Olson AJ. Small‑molecule library screening by docking with PyRx. In: Hempel JE, Williams CH, Hong CC, editors. Chemical Biology. New York, NY: Springer; 2015. p. 243–50.
  24. Onkaramurthy M, Vishwakarma KK, Singh P, Hegde S, Azeemuddin MM, Rafiq M, et al. Herbal Formulations Ameliorates Chronic Venous Insufficiency, Venotonicity and Elastase Inhibition in the Management of Varicose Veins: A Preclinical Study. Indian Journal of Pharmaceutical Sciences. 2022;84(4). doi:10.36468/pharmaceutical-sciences.1000
  25. Gwozdzinski L, Pieniazek A, Gwozdzinski K. Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs. International Journal of Molecular Sciences. 2024;25(3):1560. doi:10.3390/ijms25031560
  26. Korff T, et al. Biomechanical stretch triggers varicose vein remodeling in mice through activation of the transcription factor AP‑1. FASEB J. 2011;25.
  27. Zeng W, Fang Y, Mo S, Shen C, Yang H, Luo G, et al. The Underling Mechanisms Exploration of Rubia cordifolia L. Extract Against Rheumatoid Arthritis by Integrating Network Pharmacology and Metabolomics. Drug Design, Development and Therapy. 2023;Volume17:439-457. doi:10.2147/dddt.s388932
  28. PubChem. Available from: https://pubchem.ncbi.nlm.nih.gov/
  29. Ahmad A, Sayed A, Ginnebaugh KR, Sharma V, Suri A, Saraph A, Padhye S, Sarkar FH. Molecular docking and inhibition of matrix metalloproteinase‑2 by novel difluorinated‑benzylidene curcumin analog. Am J Transl Res. 2015;7(2):298–308. PMID:25785001
  30. Khan A, Sorour AA, E. Anton G, Lyden SP, Kirksey L. Venous Insufficiency: Endovascular and Surgical Treatment. Current Cardiology Reports. 2025;27(1). doi:10.1007/s11886-024-02155-x
  31. Costa D, Andreucci M, Ielapi N, Serraino GF, Mastroroberto P, Bracale UM, et al. Molecular Determinants of Chronic Venous Disease: A Comprehensive Review. International Journal of Molecular Sciences. 2023;24(3):1928. doi:10.3390/ijms24031928
  32. Niedzwiecki. Modulation of MMP-2 and MMP-9 by cytokines, mitogens and inhibitors in lung cancer and malignant mesothelioma cell lines. Oncology Reports. 2009;22(06). doi:10.3892/or_00000566
  33. Raffetto JD, Ligi D, Maniscalco R, Khalil RA, Mannello F. Why Venous Leg Ulcers Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment. Journal of Clinical Medicine. 2020;10(1):29. doi:10.3390/jcm10010029
  34. Smetanina MA, Shevela AI, Gavrilov KA, Filipenko ML. The genetic constituent of varicose vein pathogenesis as a key for future treatment option development. Vessel Plus. 2021. doi:10.20517/2574-1209.2021.17
  35. Chiu SC, Tsao SW, Hwang PI, Vanisree S, Chen YA, Yang NS. Differential functional genomic effects of anti-inflammatory phytocompounds on immune signaling. BMC Genomics. 2010;11(1). doi:10.1186/1471-2164-11-513
  36. Hoffmann J, Wölfle U, Schempp CM, Casetti F. Tannins fromPotentilla officinalisdisplay antiinflammatory effects in the UV erythema test and on atopic skin. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2016;14(9):917-922. doi:10.1111/ddg.12792
  37. Wu J‑H, Tung Y‑T, Chien S‑C, Wang S‑Y, Kuo Y‑H, Shyur L‑F, Chang S‑T. Effect of phytocompounds from the heartwood of Acacia confusa on inflammatory mediator production. J Agric Food Chem. 2008;56(5):1567–73. doi:10.1021/jf072959u
  38. Liang D, Liu L, Zhao Y, Luo Z, He Y, Li Y, et al. Targeting extracellular matrix through phytochemicals: a promising approach of multi-step actions on the treatment and prevention of cancer. Frontiers in Pharmacology. 2023;14. doi:10.3389/fphar.2023.1186712
  39. Patil R, Mohan M, Kasture V, Kasture S. Rubia cordifolia: a review. Oriental Pharmacy and Experimental Medicine. 2009;9(1):1-13. doi:10.3742/opem.2009.9.1.001